'The pill' for men!
BACKGROUND: Half of pregnancies in the United States are unintended. However, there are several effective methods of contraception available. Since the year 2000, there have been many new methods of birth control in the U.S., including the levonorgestrel-releasing intrauterine system, the hormonal contraceptive ring, the patch, the 91-day regimen of oral contraceptives, the hormonal implant, and a new form of female sterilization. The most popular method used by over ten million women in the US between 2006 and 2008, was the oral contraceptive pill. (Source: www.cdc.gov) However, male contraception is becoming more popular.
INTERESTING FACTS ABOUT CONTRACEPTION: Between 2006 and 2008, 99% of women who had ever had sexual intercourse had used at least one method of birth control. Some interesting facts are:
· 7.3% of women who were currently at risk of unintended pregnancy were not using a contraceptive method.
· Hormonal implants for women are 99% effective.
· Injections for women are 91-99% effective.
· Both the pill and the patch for women are 91-99% effective.
· Male condoms are 82-98% effective. Female condoms are 79-95% effective.
· Spermicides are 72-85% effective.
· Female sterilization, trans cervical sterilization, and male sterilization are all over 99% effective. (Source: www.cdc.gov)
TYPES OF MALE CONTRACEPTION: The two most common male contraceptive methods are vasectomies and condoms. They have obvious draw backs (not being reversible and condoms have a high failure rate). A study found that over 60% of men in Spain, Brazil, Mexico, and Germany were willing to use a new method of male contraception. A heat-based method could offer easily implemented birth control. Researchers have used different sources of heat to disrupt fertility: hot water, incandescent light bulbs, saunas, and ultrasounds. Optimal sperm production (spermatogenesis) requires temperatures to be below average body temperature. By warming the testicles above average, it disrupts spermatogenesis. RISUG is an option that is effective immediately right after injection procedures and lasts for ten years unless reversed. (Source: www.malecontraceptives.org)
NEW TECHNOLOGY: Oral contraceptives have been available for women since the 1960s, but for men this option has been limited. Some have tried using testosterone to decrease sperm production, but they come with a list of side effects (acne, increase risk of heart disease and prostate cancer). Spermatogenesis relies on vitamin A to allow the production of normal numbers of sperm. Researchers are developing a way to use vitamin A metabolism in the testis to regulate spermatogenesis. One recent study found that a compound that interferes with the body’s ability to use vitamin A made male mice sterile (they were receiving 8 to 16 week courses). Once they stopped giving it to the mice, they resumed making sperm. So far, the researchers have not found side effects and testosterone remained stable. Another study is working with a drug that interferes with the action of an enzyme that converts vitamin A to its biologically active form in the testis, hoping it will render men temporarily sterile. Testing is still under way. (Source: www.ncbi.nlm.nih.gov)
John Amory, MD, MPH, Physician of Internal Medicine at the University of Washington, talks about a new idea of male contraception.
Tell me about this?
Dr. Amory: The group of endocrinologists here at the University of Washington has been interested in developing a male contraceptive for over 40 years; really since the advent of the female contraceptive. The approach that has been taken historically is to use hormones to suppress spermatogenesis or sperm production. It is very analogous actually to the female pill. The female pill uses estrogen and progesterone to suppress ovulation or egg production. Male hormonal contraceptive approach uses the male hormones, testosterone plus progesterone to suppress sperm production.
What is your research?
Dr. Amory: That research has been ongoing for about 25 or 30 years. About 5 years ago, I decided to explore ways of suppressing sperm without using hormones or steroids. So, I have actually been looking at an idea to develop a male contraceptive that involves blocking the function of vitamin A in the testicle. It may surprise you to know that if you make a mouse or a rabbit vitamin A deficient, two things will happen; it will get night blindness which most people are familiar with and it will become infertile. Starting from that we decided if we could block the function of vitamin A just in the test is leaving its function intact in other tissues, maybe we could have a reversible male contraceptive that did not rely on the use of steroids such as testosterone.
What about the safety of testosterone? Are there some serious downsides?
Dr. Amory: There are concerns and the debate about whether or not to use it in older men whose testosterone may be getting lower is one thing. When you are thinking about developing a contraceptive, it has to be extraordinarily safe because there is the potential to be giving it to tens of millions of young men and they could be taking it for a long period of time. So, there are some advantages to thinking about approaches to male contraceptive development that do not rely on testosterone and that was one of my motivations for studying vitamin A.
What is the danger of taking testosterone?
Dr. Amory: The answer is we don’t know. So, there is a paradox here because most men make testosterone their entire lives from the time they go through puberty until the day they die. Whether or not it is associated with harmful outcomes is really unknown. There is concern about whether or not it might increase the risk of heart disease because it lowers the good or HDL cholesterol and then there is this association with prostate cancer, but there is a lot of uncertainty about this. So, when you see the ads for testosterone in the news, we really don’t know whether or not we are doing more good than harm. Certainly, there are short term benefits in terms of muscle mass and sex drive and those things, but what about the long term implications; it is unknown. We really need male health initiative analogous to the women’s health initiative study that was done to define the risks of testosterone.
So, I know testosterone can come in shots and you can also do a gel for men. How would you block vitamin A through a pill?
Dr. Amory: Yes, it would be a pill. Actually we have new compounds that do block and they are not just blocking vitamin A. Tissues take up vitamin A and turn it into something called retinoic acid. What we would be blocking is the conversion of vitamin A, or retinol to retinoic acid in the tissue. This would be a pill; probably a daily pill and eventually we could develop a 3 monthly formulation similar to Depo-Provera which is very popular for women.
Which comes to the fact, and I have said this to women, and they respond, “we would never trust a man to take a pill.” What is your response to that?
Dr. Amory: I think that is a valid point. The pill would be good for some men. There are some men who probably take a pill religiously. Once we get the pill developed, we will be looking at longer acting injectable forms and maybe even implants. There are two yearly implants that women take and those are ideal because they take remembering to take your pill out of the equation. So the hope is that we could develop the pill that we are working on into something that would be longer acting for men. I will tell you a funny story… So we have done studies with hormonal contraceptives using implants and the men really like the implants because they can show them off at cocktail parties. They are put on the inner aspect of the upper arm and so it is kind of an excuse to point out their bicep to women. Also it is nice because the women can feel the implant; rest assured that the man was actually using contraception.
It seems a little unfair these testosterone implants, because of the side effects: more energy, losing weight and building muscle mass. Don’t you think?
Dr. Amory: It is beneficial. It is unfair. You bring up a good point about side effects. I mean people often ask me why we need a male pill. We have got very effective female contraception. Well, one of the reasons is the side effects that the female contraceptives cause. Some of them are annoyances and some of them can be quite serious. As you know, sometimes women using contraceptives will get blood clots and then they can’t use contraceptives. If you are in a couple where the woman has a reason not to use a contraceptive, the availability of a male contraceptive would be quite helpful.
Would there be any other risks to blocking vitamin A?
Dr. Amory: There are a couple of tissues we are looking at very carefully. The first is the eye of course. We would not want to affect vision. Fortunately, the step that we are blocking seems to be below the step where vitamin A is needed in the eyes. So we think that the eye should be fine. And then the other is the liver. So, in early versions of the compound that we are using caused some fat accumulation in the liver which long term could be harmful. We are hoping that our newer compounds will show less of those effects.
Now, the man we are talking to next, Michael?
What is Mike Leaman, doing right now?
Dr. Amory: Mike has been on probably 5 or 6 of our contraceptive trials over the last 15 years. So, just so you understand, the hormonal contraceptive trials, those are actually in clinical testing. We have done several of those trials and Mike has participated in those trials. What that entails for a man is, he usually comes in, we make sure he is healthy, and that it is unlikely that he is going to be harmed by participation in the study; then he gets either injections or gels of testosterone plus or minus a progestin over a period of about 6 months and then comes in monthly and we check his sperm counts and we watch them suppress to zero and then after 6 months of treatment. We will remove the treatment and watch the sperm counts come back up; just to assure that it works and that it is reversible. You might ask why is this not on the market? Well the problem with this approach is that it only works in about 80 to 90% of men.
Why does it not work on all?
Dr. Amory: We don’t know. So that has been the real bugaboo with this field. For the last 30 years a subset of men suppress their sperm counts, but not all the way to zero. Men make about 1000 sperm a second. So you really want to get the sperm count pretty much down to zero to ensure that they are effectively contraceptive. Women make one egg a month and I think for some reasons it has been easier to suppress the production of an egg a month than it is to suppress sperm production which is such as robust phenomenon.
The blocking the vitamin A is not in clinical trial yet?
Dr. Amory: We are testing. We are developing new drugs. We are testing them in mice and if we have a promising compound in mice, hopefully, we will be able to take it to humans, probably in the next 3 to 5 years.
You are testing in mice?
Dr. Amory: Oh, we use C-57 black 6 mice.
How temporary is it?
Dr. Amory: So the kinetics of this takes about 72 days from a sperm to go from its stem cell state to its mature state where it is ready to fertilize an egg. When you start one of these drugs, you are actually not contracted for about 2 to 3 months. It turns out, then you take the drug and then when you stop it, it takes about 2 to 3 months actually for you to become fertile again. So, there is a delay in the onset and a delay in the offset of this. It is really not for the person who is looking for contraception for a single encounter. It really is best viewed as something that somebody in a couple would use, probably a stable monogamous relationship, because of course none of these things will protect against sexually transmitted infections.
FOR MORE INFORMATION, PLEASE CONTACT:
John K. Amory, MD, MPH
University of Washington
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